Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

ABSTRACT Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to

11q13–q23 (_EVR1_; OMIM 133780, ref. 1), Xp11.4 (_EVR2_; OMIM 305390, ref. 2) and 11p13–12 (_EVR3_; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13–23 locus for autosomal

dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb. Mutations in _FZD4_, encoding the putative Wnt receptor frizzled-4,

segregated completely with affected individuals in the family and were detected in affected individuals from an additional unrelated family, but not in normal controls. FZD genes encode Wnt

receptors, which are implicated in development and carcinogenesis. Injection of wildtype and mutated _FZD4_ into _Xenopus laevis_ embryos revealed that wildtype, but not mutant, frizzled-4

activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca2+ signaling pathway. In one of the mutants, altered subcellular

trafficking led to defective signaling. These findings support a function for frizzled-4 in retinal angiogenesis and establish the first association between a Wnt receptor and human disease.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS _RS1H__−/Y_ EXON 3-DEL RAT MODEL OF X-LINKED RETINOSCHISIS WITH EARLY ONSET AND RAPID PHENOTYPE IS RESCUED BY _RS1_ SUPPLEMENTATION Article

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RHODOPSIN MUTANTS IN MOUSE MODELS OF AUTOSOMAL DOMINANT RETINITIS PIGMENTOSA Article Open access 16 February 2024 ACCESSION CODES ACCESSIONS GENBANK/EMBL/DDBJ * AB029451 * AF117388 *

AJ251750 * AK000684 * AK024853 * FLJ22104 * NM_012193 * NM_022918 * NP_001457 * NP_003459 * NP_003496 * NP_003497 * NP_003498 * NP_003499 * NP_005622 * NP_009128 * NP_032081 * NP_036325 *

NP_059108 * NP_114072 * NT_009184 CHANGE HISTORY * _ 22 AUGUST 2002 Changed Wn to Wnt and changed vasculative to vasculature _ NOTES * NOTE: There were two typographical errors in the AOP

version of this article, which have since been corrected. On page 1, 'Wn' in line 12 was replaced with 'Wnt', and 'vasculative' in line 10 was replaced with

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MacFarlane, B. Payne, C. Radomski, M. Mattice, A. Hogan, P. Samra, and G. Donaldson at Xenon Genetics and C. Tatlidil at Dalhousie University for technical support; F. Mikelberg for

discussion; and the members of the affected families for their enthusiasm and participation. This work was supported in part by a grant from the Nova Scotia Health Research Foundation and

the IWK Health Centre to J.R. B.S.S. was supported in part by the Fight for Sight research division of Prevent Blindness America. R.T.M. is an Investigator of the Howard Hughes Medical

Institute. M.R.H. holds a Canada Research Chair. A.K. was supported by an US National Institutes of Health Reproductive Biology Training Grant. AUTHOR INFORMATION Author notes * Johane

Robitaille and Marcia L.E. MacDonald: These two authors contributed equally to the work. AUTHORS AND AFFILIATIONS * Department of Ophthalmology, Izaak Walton Killam (IWK) Health Centre,

Dalhousie University, Halifax, B3H 2Y9, Nova Scotia, Canada Johane Robitaille, Duane L. Guernsey & Binyou Zheng * Department of Pathology, Division of Molecular Pathology and Molecular

Genetics, Dalhousie University, Halifax, B3H 4H7, Nova Scotia, Canada Johane Robitaille & Duane L. Guernsey * Xenon Genetics, Inc., Burnaby, V5G 4W8, British Columbia, Canada Marcia L.E.

MacDonald, Jutta Zeisler, Marie-Pierre Dubé, Lin-Hua Zhang, Roshni R. Singaraja, Simon N. Pimstone, Michael R. Hayden, Y. Paul Goldberg & Mark E. Samuels * Department of Pharmacology,

Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington, USA Ajamete Kaykas, Laird C. Sheldahl & Randall T. Moon * Department of Ophthalmology,

University of Western Ontario, London, Ontario, Canada Lee F. Siebert * Department of Ophthalmology, QEII Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada Ann Hoskin-Mott

* William Beaumont Hospital, Royal Oak, Michigan, USA Michael T. Trese * Department of Biological Sciences, Oakland University, Rochester, Michigan, USA Barkur S. Shastry * Department of

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Robitaille, J., MacDonald, M., Kaykas, A. _et al._ Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative

vitreoretinopathy. _Nat Genet_ 32, 326–330 (2002). https://doi.org/10.1038/ng957 Download citation * Received: 23 March 2002 * Accepted: 16 July 2002 * Published: 12 August 2002 * Issue

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